The treatment of pain conditions is of utmost importance in medicine, leading to a worldwide need for additional therapies for its treatment and prevention.
Pain is the most common symptom for which patients seek medical attention. Although there is no exact definition it can be defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (International Association for the Study of Pain, IASP).
Pain is a very relevant symptom that presents a complex pathogenesis. Its presence is described in a large number of syndromes and diseases in medicine. In severe forms, pain translates into disabilities of diverse nature, difficulty in performing daily activities, interference with mood, professional performance and social relations.
Furthermore, the interpretation of pain varies from individual to individual, and within the individual himself, at different times of his life, depending on varying physical, biological, socio-cultural and emotional conditions.
Regarding the topographic distribution it is possible to distinguish three types of pain: peripheral pain, central pain and psychogenic pain.
Peripheral pain is the result of an organic disorder in peripheral nerve fibers, which, while transmitting nerve impulses, originate the sensation of pain. Peripheral pain further divides into superficial peripheral pain and deep peripheral pain. The first is acute and penetrating and it is located at the point of origin. Deep peripheral pain may be classified as somatic or visceral. Somatic deep peripheral pain can be localised (pain is located at the point of origin of the painful stimulus) or radiating (pain is diffuse and distant from the point of origin of the painful stimulus). Finally, deep visceral peripheral pain has a difficult topography to limit.
Central pain is a spontaneous pain resulting from neurological injury of central nerve centres such as the spinal cord, medulla oblongata, the thalamus or the cerebral cortex.
Psychogenic pain is defined as a painful sensation that does not have an organic substrate. It is any pain that is exclusively mental, which acquires a specific anatomical location.
From the pathophysiological point of view, pain can be nociceptive or neuropathic.
Nociceptive pain can be defined as pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors. Nociceptive pain can be classified as somatic or visceral. Somatic pain is due to activation of the nociceptive receptors in somatic tissues, such as bone, joint, muscle or skin. In visceral pain the visceral nociceptors are activated by different pathological mechanisms (e.g. mechanical injury, inflammation, radiation, toxic agents). Both visceral and somatic nociceptive pain can be acute or chronic. Visceral pain is more difficult to characterise and less sensitive to usual pain treatment. Some pain syndromes (e.g., cancer pain) include elements of both visceral and somatic nociceptive pain.
Neuropathic pain can be defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system (i.e. peripheral nerve, the dorsal root ganglion or dorsal root or the central nervous system).
Almost any of the pathological processes known to create damage or dysfunction to neural tissue can be considered as potential causes for neuropathic pain: viral, bacterial, aseptic inflammation, pressure due to neoplasm or other structural lesions, degenerative, ischemia, autoimmune, toxic, traumatic or endocrine/metabolic mechanisms all have been implicated in the production of neuropathic pain.
However, the most commonly studied neuropathic pain conditions include diabetic neuropathic pain (diabetic NP), post-herpetic neuralgia (PHN), trigeminal neuralgia and central neuropathic pain (spinal cord injury (SCI), central post-stroke pain (CPSP) and multiple sclerosis associated pain).
Other neuropathic pain conditions include neuropathy associated with HIV infection (HIV neuropathy), post-traumatic or post-surgical neuropathic pain, chronic radiculopathy, cancer associated neuropathic pain, phantom pain and multi-aetiology neuropathic pain.
Neuropathy is a functional disorder or pathological change that affects the nerves. It is called mononeuropathy if it involves a single nerve trunk, multiple mononeuropathy if it successively involves several nerve trunks and polyneuropathy if it involves, diffusely and bilaterally, several nerve trunks.
Peripheral neuropathies may be sensory, motor or autonomic. The most frequent motor manifestations are muscle spasms, clonus, fasciculations, amyotrophy and the loss of muscle strength or dexterity.
Negative sensory manifestations include hypoalgesia and hypoesthesia. In turn, positive sensory manifestations include paresthesia, dysesthesia, hyperpathia, hyperalgesia and allodynia, aside from the sensation of pricking, tingling or tinnitus. Examples of neuropathy include, peripheral polyneuropathy, characterised by a burning or needle pricking sensation in the feet and fingertips, which is worsened by walking, allodynia, feet hypoesthesia, and absence of Achilles reflex; trigeminal neuralgia, characterised by severe acute pain, shock-like, with duration of seconds in the upper lip and nose, which worsens with chewing or brushing and which is not accompanied by changes in the neurological examination; carpal tunnel syndrome, characterised by acute pain, tingling sensations and reduced sensitivity in the 1st, 2nd and 3rd fingers and palmar surface of the hand, that worsens at night, with decreased muscle strength in thumb abduction and positive Phalen test; mononeuropathy of the lateral cutaneous nerve of the thigh, characterised by a burning and pricking sensation to the side of the thigh and presence of a circumscribed area of cutaneous hypersensitivity; postherpetic neuralgia, characterised by a burning pain with banner-like distribution on the thoracic region after the appearance of vesicles, which does not improve after skin healing, hyperchromic skin spots and allodynia.
The impact of pain on individual and social welfare has increased in recent decades.
To this regard, neuropathic pain is widely recognised as one of the most difficult pain syndromes to manage, and outcomes often are unsatisfactory. Neuropathic pain is estimated to afflict as high as 7-8% of the general population in Europe (European Federation of Neurological Societies guidelines on the pharmacological treatment of neuropathic pain, 2010).
Management of neuropathic pain is a complicated endeavour and often is frustrating to patient and physician alike. Drugs with mechanisms of action that are not aimed at changing the underlying physiopathological processes, or that are administered at sub-therapeutic doses, are frequently used in the treatment of pain, and a fortiori of neuropathic pain.
This stems from the relatively incomplete understanding of mechanisms of actions of drugs and the limited efficacy of currently available analgesics. Therapeutic approaches vary greatly among physicians and recalcitrant chronic pain syndromes warrant an interdisciplinary approach and more potent pharmacotherapies.
The use of analgesic medications follows a step-wise approach. The 1st step corresponds to mild pain, and should be treated with non-opioid analgesic drugs (anti-inflammatory drugs and paracetamol); the 2nd is moderate pain, for which weak opioids are indicated and, in the third step, for severe pain, strong opioids are indicated. Depending on the intensity of pain, therapy should be initiated at the corresponding level, with appropriate doses. If the pain persist or worsens, drug doses should be optimised.
Analgesic drugs can be distributed in two large groups: non-opioid and opioid analgesic drugs.
Non-opioid analgesic drugs include paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs). Paracetamol does not have a well known mechanism of action although a central action is assumed. The administration of large doses either acutely or chronically, involves a risk of hepatotoxicity associated with depletion of sulfhydryl radicals.
Nonsteroidal anti-inflammatory drugs act by inhibiting cyclooxygenase (COX), inhibiting the synthesis of prostaglandins (PG) involved in the inflammatory process and in pain. They may be non-selective, inhibiting COX1 and COX2, as acetylsalicylic acid (AAS), ibuprofen or diclofenac, or selective, inhibiting only COX2, as celecoxib, rofecoxib or etoricoxib. Nonsteroidal anti-inflammatory drugs present several side effects, including gastrointestinal (nausea, epigastralgia, ulceration, bleeding), renal (acute renal failure, interstitial nephritis), haematological (platelet anti-aggregation, haemorrhage) or hypersensitivity reactions. These effects are most notorious with non-selective NSAIDs. The main side effect with COX2 inhibitors is an increased cardiovascular risk, by inhibiting prostacyclin. Nonsteroidal anti-inflammatory drugs treatment is associated with an increased risk of gastrointestinal adverse reactions.
The so-called weak opioid drugs include drugs like tramadol, hydrocodone and dextropropoxyphene. These drugs have a maximum posology due to the increased incidence of adverse reactions at high doses. Tramadol is a synthetic derivative of codeine that acts by binding to opioid μ receptors and inhibiting neuronal reuptake of serotonin. Tramadol is metabolised in the liver and undergoes renal elimination, therefore it may require dose decrease or prolonged interval between doses in patients with kidney or renal failure.
Hydrocodone is a synthetic derivative of codeine and dextropropoxyphene and presents a structure similar to methadone. Patients with mild to moderate pain should be treated with a weak opioid associated with a NSAID or paracetamol. If pain cannot be controlled at therapeutic doses, a switch to another drug in this group should not be considered and more potent opioids should be used.
Opioids act by binding to receptors μ, κ, and δ and may be classified, according to their intrinsic activity, in agonists (morphine, fentanyl, methadone, oxycodone, hydromorphone and pethidine), partial agonist/antagonist (buprenorphine) and agonist/antagonist (pentazocine). A pure agonist is a drug which exerts effect on μ receptors and on the other receptors. A partial agonist/antagonist exerts a partial agonist effect on a receptor and antagonist effect in at least one receptor, and an agonist/antagonist exerts a pure agonist effect on a receptor and an antagonist effect on at least one receptor.
Opioids induce predictable undesirable side effects, which if not minimised can hamper dose titration and the patient's treatment compliance. Side effects include respiratory depression, nausea and vomiting, constipation, urinary retention, euphoria, sedation, miosis, antitussive action, hypotension, bradycardia, cognitive changes (hallucinations, delusional ideas), hyperalgesia, myoclonus, dyspepsia, pruritus, tolerance and dependence.
Morphine can be administered by oral or parenteral route (subcutaneous and intravenous). Intravenous administration requires specific care and its use is limited to the inpatient setting. For subcutaneous administration infusion pumps are used.
Tricyclic antidepressants (amitriptyline, nortriptyline and desipramine) are used in combination with analgesic drugs, particularly in combination with opioids and mostly in the treatment of neuropathic pain. Due to their anti-cholinergic action, adverse reactions include constipation, xerostomia, urinary retention and tachycardia.
Anticonvulsants (carbamazepine, oxcarbazepine, phenytoin, sodium valproate, clonazepam, lamotrigine, gabapentin, pregabalin) are also used in the treatment of pain, especially neuropathic pain. Carbamazepine and phenytoin can cause liver toxicity, leukopaenia and thrombocytopaenia, thus requiring monitoring of serum concentrations.
Corticosteroids, of which dexamethasone is most often used for the treatment of pain, are associated with the onset of gastrointestinal disorders, diabetes mellitus, neuro-psychiatric disorders and proximal myopathy.
Therefore it is still a need in the state of the art to find new therapeutic approaches for the treatment of pain, not only as a symptom of disease, but as a disease itself.
The problem that the present invention solves is the provision of an alternative, new and effective agent for the treatment of pain, which alone or in combination with other analgesic agents provides an effective treatment of pain with reduced side effects while maintaining the desirable analgesic activity.